As of last week critics of the US FDA’s generous approach to approving cancer drugs have another reason to wonder what it will take for the agency to revoke a conditional approval: the failure of Keytruda ’s gastric cancer trial Keynote-061.

This result, in a second-line setting, comes hot on the heels of Bavencio ’s flop in the third-line Javelin Gastric 300 trial, providing strong evidence that checkpoint blockade alone simply does not work in this cancer type. And yet Keytruda , having secured a flimsy accelerated third-line US approval less than two months ago, looks safe in its market niche.

Part of the issue lies in patient demand, of course. With doctors increasingly speaking of patients clamouring for anti-PD-(L)1 therapy, for approved as well as unapproved cancer types, it would harm regulators’ image to start restricting access to these drugs, which in some settings have clearly proved revolutionary.

But there has to come a point where science must back up the hype, and if it does not then everyone risks looking foolish. This had already been seen in head and neck cancer, where failure of the potentially confirmatory trial Keynote-040 did absolutely nothing to the approved status of Merck & Co ’s Keytruda .

And in bladder cancer the FDA went out of its way to grant accelerated approvals, based solely on remission rates, to Roche ’s Tecentriq , Bristol-Myers Squibb’s Opdivo , Astrazeneca ’s Imfinzi and Merck KGaA /Pfizer ’s Bavencio – just before the Roche drug flunked its confirmatory Imvigor-211 trial. All remain on the market.

Merck & Co said on Thursday that in the second-line Keynote-061 trial Keytruda had failed to extend overall and progression-free survival versus paclitaxel chemo – despite the company upping the chances of success by enrolling only patients expressing PD-L1 .

The group somewhat optimistically pointed to the ongoing Keynote-062 trial, in first-line gastric cancer, where Keytruda is being given either as monotherapy or combined with chemo. If PD-(L)1 blockade simply does not work in this cancer then this study too should be written off by investors.

One problem is having to beat chemo, which appears to be moderately effective even in third-line gastric cancer. And there are reasons why Opdivo ’s Attraction-2 trial – in an exclusively Asian population and versus placebo – yielded a survival advantage (Bavencio’s gastric failure calls into question rival approvals, November 29, 2017).

Studies of Keytruda in gastric cancer

Study

Setting

Trial ID

Data

Keynote-059

Uncontrolled, several cohorts, including 3rd-line monotherapy

NCT02335411

ORR 11.2%, basis for accelerated US approval

Keynote-061

Vs chemo, 2nd-line, PD-L1 +ve

NCT02370498

Failed to extend OS or PFS

Keynote-062

Monotherapy or on top of chemo, vs chemo, 1st-line, PD-L1 +ve

NCT02494583

2019

Keynote-585

On top of chemo, vs chemo, neoadjuvant or adjuvant

NCT03221426

2023

If accelerated approvals now guarantee checkpoint inhibitors a permanent green light then investors tracking other approvals on this basis can rest easy. These include Opdivo ’s thumbs up in liver cancer on the basis of Checkmate-040, Keytruda ’s go-ahead in mismatch repair-deficient tumours, and of course Bavencio ’s registration in its first indication, Merkel cell carcinoma.

As a strategy, therefore, it still makes sense for checkpoint inhibitor latecomers to secure an accelerated approval in a rare cancer just to get a drug into the market. This seems to be the plan for Sanofi and Regeneron , which last week initiated a rolling US BLA for cemiplimab – in advanced cutaneous squamous cell carcinoma.

If it is approved cemiplimab stands to become the sixth anti-PD-(L)1 agent to hit the market. Regeneron seems undeterred by such a disadvantage, today striking a deal with the private group ISA Pharmaceuticals to combine cemiplimab with ISA101 , a vaccine targeting HPV16-induced cancers.

With the FDA apparently willing to let approvals granted on flimsy grounds stand there is still a market worth playing for. That is, of course, until the ultimate arbiters – the payers – have their say.